Cortical ß Power Reflects a Neural Implementation of Decision Boundary Collapse in Speeded Decisions.

A prominent account of decision-making assumes that information is accumulated until a fixed response threshold is crossed. However, many decisions require weighting of information appropriately against time. Collapsing response thresholds are a mathematically optimal solution to this decision problem. However, our understanding of the neurocomputational mechanisms underlying dynamic response thresholds remains significantly incomplete. To investigate this issue, we used a multistage drift-diffusion model (DDM) and also analyzed EEG ß power lateralization (BPL). The latter served as a neural proxy for decision signals. We analyzed a large dataset (n = 863; 434 females and 429 males) from a speeded flanker task and data from an independent confirmation sample (n = 119; 70 females and 49 males). We showed that a DDM with collapsing decision thresholds, a process wherein the decision boundary reduces over time, captured participants' time-dependent decision policy more accurately than a model with fixed thresholds. Previous research suggests that BPL over motor cortices reflects features of a decision signal and that its peak, coinciding with the motor response, may serve as a neural proxy for the decision threshold. We show that BPL around the response decreased with increasing RTs. Together, our findings offer compelling evidence for the existence of collapsing decision thresholds in decision-making processes.

Transdiagnostic inflexible learning dynamics explain deficits in depression and schizophrenia.

Deficits in reward learning are core symptoms across many mental disorders. Recent work suggests that such learning impairments arise by a diminished ability to use reward history to guide behaviour, but the neuro-computational mechanisms through which these impairments emerge remain unclear. Moreover, limited work has taken a transdiagnostic approach to investigate whether the psychological and neural mechanisms that give rise to learning deficits are shared across forms of psychopathology. To provide insight into this issue, we explored probabilistic reward learning in patients diagnosed with major depressive disorder (n = 33) or schizophrenia (n = 24) and 33 matched healthy controls by combining computational modelling and single-trial EEG regression. In our task, participants had to integrate the reward history of a stimulus to decide whether it is worthwhile to gamble on it. Adaptive learning in this task is achieved through dynamic learning rates that are maximal on the first encounters with a given stimulus and decay with increasing stimulus repetitions. Hence, over the course of learning, choice preferences would ideally stabilize and be less susceptible to misleading information. We show evidence of reduced learning dynamics, whereby both patient groups demonstrated hypersensitive learning (i.e. less decaying learning rates), rendering their choices more susceptible to misleading feedback. Moreover, there was a schizophrenia-specific approach bias and a depression-specific heightened sensitivity to disconfirmational feedback (factual losses and counterfactual wins). The inflexible learning in both patient groups was accompanied by altered neural processing, including no tracking of expected values in either patient group. Taken together, our results thus provide evidence that reduced trial-by-trial learning dynamics reflect a convergent deficit across depression and schizophrenia. Moreover, we identified disorder distinct learning deficits.

Unraveling the influence of trial-based motivational changes on performance monitoring stages in a flanker task.

Performance monitoring (PM) is a vital component of adaptive behavior and known to be influenced by motivation. We examined effects of potential gain (PG) and loss avoidance (LA) on neural correlates of PM at different processing stages, using a task with trial-based changes in these motivational contexts. Findings suggest more attention is allocated to the PG context, with higher amplitudes for respective correlates of stimulus and feedback processing. The PG context favored rapid responses, while the LA context emphasized accurate responses. Lower response thresholds in the PG context after correct responses derived from a drift-diffusion model also indicate a more approach-oriented response style in the PG context. This cognitive shift is mirrored in neural correlates: negative feedback in the PG context elicited a higher feedback-related negativity (FRN) and higher theta power, whereas positive feedback in the LA context elicited higher P3a and P3b amplitudes, as well as higher theta power. There was no effect of motivational context on response-locked brain activity. Given the similar frequency of negative feedback in both contexts, the elevated FRN and theta power in PG trials cannot be attributed to variations in reward prediction error. The observed variations in the FRN indicate that the effect of outcome valence is modulated by motivational salience.

In vivo fluorescent labeling and tracking of extracellular matrix.

Connective tissues are essential building blocks for organ development, repair and regeneration. However, we are at the early stages of understanding connective tissue dynamics. Here, we detail a method that enables in vivo fate mapping of organ extracellular matrix (ECM) by taking advantage of a crosslinking chemical reaction between amine groups and N-hydroxysuccinimide esters. This methodology enables robust labeling of ECM proteins, which complement previous affinity-based single-protein methods. This protocol is intended for entry-level scientists and the labeling step takes between 5 and 10 min. ECM 'tagging' with fluorophores using N-hydroxysuccinimide esters enables visualization of ECM spatial modifications and is particularly useful to study connective tissue dynamics in organ fibrosis, tumor stroma formation, wound healing and regeneration. This in vivo chemical fate mapping methodology is highly versatile, regardless of the tissue/organ system, and complements cellular fate-mapping techniques. Furthermore, as the basic chemistry of proteins is highly conserved between species, this method is also suitable for cross-species comparative studies of ECM dynamics.

GDF15 Promotes the Osteogenic Cell Fate of Periodontal Ligament Fibroblasts, thus Affecting Their Mechanobiological Response.

Periodontal ligament fibroblasts (PdLFs) exert important functions in oral tissue and bone remodeling following mechanical forces, which are specifically applied during orthodontic tooth movement (OTM). Located between the teeth and the alveolar bone, mechanical stress activates the mechanomodulatory functions of PdLFs including regulating local inflammation and activating further bone-remodeling cells. Previous studies suggested growth differentiation factor 15 (GDF15) as an important pro-inflammatory regulator during the PdLF mechanoresponse. GDF15 exerts its effects through both intracrine signaling and receptor binding, possibly even in an autocrine manner. The extent to which PdLFs are susceptible to extracellular GDF15 has not yet been investigated. Thus, our study aims to examine the influence of GDF15 exposure on the cellular properties of PdLFs and their mechanoresponse, which seems particularly relevant regarding disease- and aging-associated elevated GDF15 serum levels. Therefore, in addition to investigating potential GDF15 receptors, we analyzed its impact on the proliferation, survival, senescence, and differentiation of human PdLFs, demonstrating a pro-osteogenic effect upon long-term stimulation. Furthermore, we observed altered force-related inflammation and impaired osteoclast differentiation. Overall, our data suggest a major impact of extracellular GDF15 on PdLF differentiation and their mechanoresponse.

Neural evidence for age-related deficits in the representation of state spaces.

Under high cognitive demands, older adults tend to resort to simpler, habitual, or model-free decision strategies. This age-related shift in decision behavior has been attributed to deficits in the representation of the cognitive maps, or state spaces, necessary for more complex model-based decision-making. Yet, the neural mechanisms behind this shift remain unclear. In this study, we used a modified 2-stage Markov task in combination with computational modeling and single-trial EEG analyses to establish neural markers of age-related changes in goal-directed decision-making under different demands on the representation of state spaces. Our results reveal that the shift to simpler decision strategies in older adults is due to (i) impairments in the representation of the transition structure of the task and (ii) a diminished signaling of the reward value associated with decision options. In line with the diminished state space hypothesis of human aging, our findings suggest that deficits in goal-directed, model-based behavior in older adults result from impairments in the representation of state spaces of cognitive tasks.

Feedback-related EEG dynamics separately reflect decision parameters, biases, and future choices.

Optimal decision making in complex environments requires dynamic learning from unexpected events. To speed up learning, we should heavily weight information that indicates state-action-outcome contingency changes and ignore uninformative fluctuations in the environment. Often, however, unrelated information is hard to ignore and can potentially bias our learning. Here we used computational modelling and EEG to investigate learning behaviour in a modified probabilistic choice task that introduced two task-irrelevant factors that were uninformative for optimal task performance, but nevertheless could potentially bias learning: pay-out magnitudes were varied randomly and, occasionally, feedback presentation was enhanced by visual surprise. We found that participants' overall good learning performance was biased by distinct effects of these non-normative factors. On the neural level, these parameters are represented in a dynamic and spatiotemporally dissociable sequence of EEG activity. Later in feedback processing the different streams converged on a central to centroparietal positivity reflecting a signal that is interpreted by downstream learning processes that adjust future behaviour.

Disentangling performance-monitoring signals encoded in feedback-related EEG dynamics.

The feedback-related negativity (FRN) is a well-established electrophysiological correlate of feedback-processing. However, there is still an ongoing debate whether the FRN is driven by negative or positive reward prediction errors (RPE), valence of feedback, or mere surprise. Our study disentangles independent contributions of valence, surprise, and RPE on the feedback-related neuronal signal including the FRN and P3 components using the statistical power of a sample of N = 992 healthy individuals. The participants performed a modified time-estimation task, while EEG from 64 scalp electrodes was recorded. Our results show that valence coding is present during the FRN with larger amplitudes for negative feedback. The FRN is further modulated by surprise in a valence-dependent way being more positive-going for surprising positive outcomes. The P3 was strongly driven by both global and local surprise, with larger amplitudes for unexpected feedback and local deviants. Behavioral adaptations after feedback and FRN just show small associations. Results support the theory of the FRN as a representation of a signed RPE. Additionally, our data indicates that surprising positive feedback enhances the EEG response in the time window of the P3. These results corroborate previous findings linking the P3 to the evaluation of PEs in decision making and learning tasks.

Neutrophils direct preexisting matrix to initiate repair in damaged tissues.

Internal organs heal injuries with new connective tissue, but the cellular and molecular events of this process remain obscure. By tagging extracellular matrix around the mesothelium lining in mouse peritoneum, liver and cecum, here we show that preexisting matrix was transferred across organs into wounds in various injury models. Using proteomics, genetic lineage-tracing and selective injury in juxtaposed organs, we found that the tissue of origin for the transferred matrix likely dictated the scarring or regeneration of the healing tissue. Single-cell RNA sequencing and genetic and chemical screens indicated that the preexisting matrix was transferred by neutrophils dependent on the HSF-integrin AM/B2-kindlin3 cascade. Pharmacologic inhibition of this axis prevented matrix transfer and the formation of peritoneal adhesions. Matrix transfer was thus an early event of wound repair and provides a therapeutic window to dampen scaring across a range of conditions.

Unbiased post-error slowing in interference tasks: A confound and a simple solution.

We typically slow down after committing an error, an effect termed post-error slowing (PES). Traditionally, PES has been calculated by subtracting post-correct from post-error RTs. Dutilh et al. (Journal of Mathematical Psychology, 56(3), 208-216, 2012), however, showed PES values calculated in this way are potentially biased. Therefore, they proposed to compute robust PES scores by subtracting pre-error RTs from post-error RTs. Based on data from a large-scale study using the flanker task, we show that both traditional and robust PES estimates can be biased. The source of the bias are differential imbalances in the percentage of congruent vs. incongruent post-correct, pre-error, and post-error trials. Specifically, we found that post-correct, pre-error, and post-error trials were more likely to be congruent than incongruent, with the size of the imbalance depending on the trial type as well as the length of the response-stimulus interval (RSI). In our study, for trials preceded by a 700-ms RSI, the percentages of congruent trials were 62% for post-correct trials, 66% for pre-error trials, and 56% for post-error trials. Relative to unbiased estimates, these imbalances inflated traditional PES estimates by 37% (9 ms) and robust PES estimates by 42% (16 ms) when individual-participant means were calculated. When individual-participant medians were calculated, the biases were even more pronounced (40% and 50% inflation, respectively). To obtain unbiased PES scores for interference tasks, we propose to compute unweighted individual-participant means by initially calculating mean RTs for congruent and incongruent trials separately, before averaging congruent and incongruent mean RTs to calculate means for post-correct, pre-error and post-error trials.

Performance monitoring in obsessive-compulsive disorder: Insights from internal capsule/nucleus accumbens deep brain stimulation.

BACKGROUND: Symptoms of obsessive-compulsive disorder (OCD) are partly related to impaired cognitive control processes and theta modulations constitute an important electrophysiological marker for cognitive control processes such as signaling negative performance feedback in a fronto-striatal network. Deep brain stimulation (DBS) targeting the anterior limb of the internal capsule (ALIC)/nucleus accumbens (NAc) shows clinical efficacy in OCD, while the exact influence on the performance monitoring system remains largely unknown. METHODS: Seventeen patients with treatment-refractory OCD performed a probabilistic reinforcement learning task. Analyses were focused on 4-8 Hz (theta) power, intertrial phase coherence (ITPC) and debiased weighted Phase-Lag Index (dwPLI) in response to negative performance feedback. Combined EEG and local field potential (LFP) recordings were obtained shortly after DBS electrode implantation to investigate fronto-striatal network modulations. To assess the impact of clinically effective DBS on negative performance feedback modulations, EEG recordings were obtained pre-surgery and at follow-up with DBS on and off. RESULTS: Medial frontal cortex ITPC, striatal ITPC and striato-frontal dwPLI were increased following negative performance feedback. Decreased right-lateralized dwPLI was associated with pre-surgery symptom severity. ITPC was globally decreased during DBS-off. CONCLUSION: We observed a theta phase coherence mediated fronto-striatal performance monitoring network. Within this network, decreased connectivity was related to increased OCD symptomatology, consistent with the idea of impaired cognitive control in OCD. While ALIC/NAc DBS decreased theta network activity globally, this effect was unrelated to clinical efficacy and performance monitoring.

Post-surgical adhesions are triggered by calcium-dependent membrane bridges between mesothelial surfaces.

Surgical adhesions are bands of scar tissues that abnormally conjoin organ surfaces. Adhesions are a major cause of post-operative and dialysis-related complications, yet their patho-mechanism remains elusive, and prevention agents in clinical trials have thus far failed to achieve efficacy. Here, we uncover the adhesion initiation mechanism by coating beads with human mesothelial cells that normally line organ surfaces, and viewing them under adhesion stimuli. We document expansive membrane protrusions from mesothelia that tether beads with massive accompanying adherence forces. Membrane protrusions precede matrix deposition, and can transmit adhesion stimuli to healthy surfaces. We identify cytoskeletal effectors and calcium signaling as molecular triggers that initiate surgical adhesions. A single, localized dose targeting these early germinal events completely prevented adhesions in a preclinical mouse model, and in human assays. Our findings classifies the adhesion pathology as originating from mesothelial membrane bridges and offer a radically new therapeutic approach to treat adhesions.

Decreased transfer of value to action in Tourette syndrome.

OBJECTIVE: Tourette syndrome is a neurodevelopmental disorder putatively associated with a hyperdopaminergic state. Therefore, it seems plausible that excessive dopamine transmission in Tourette syndrome alters the ability to learn based on rewards and punishments. We tested whether Tourette syndrome patients exhibited altered reinforcement learning and corresponding feedback-related EEG deflections. METHODS: We used a reinforcement learning task providing factual and counterfactual feedback in a sample of 15 Tourette syndrome patients and matched healthy controls whilst recording EEG. The paradigm presented various reward probabilities to enforce adaptive adjustments. We employed a computational model to derive estimates of the prediction error, which we used for single-trial regression analysis of the EEG data. RESULTS: We found that Tourette syndrome patients showed increased choice stochasticity compared to controls. The feedback-related negativity represented an axiomatic prediction error for factual feedback and did not differ between groups. We observed attenuated P3a modulation specifically for factual feedback in Tourette syndrome patients, representing impaired coding of attention allocation. CONCLUSION: Our findings indicate that cortical prediction error coding is unaffected by Tourette syndrome. Nonetheless, the transfer of learned values into choice formation is degraded, in line with a hyperdopaminergic state.

The feedback-related negativity indexes prediction error in active but not observational learning.

Reinforcement learning (RL) theory states that learning is driven by prediction errors (PEs)-the discrepancy between the predicted and actual outcome of an action. When participants learn from their own actions, PEs correlate with the feedback-related negativity (FRN), but it is not clear if the FRN reflects a PE in observational learning. We use a model-based regression analysis of single-trial event-related potentials to determine if the FRN in observational learning is PE driven. Twenty participants (16 female) learned the stimulus-outcome contingencies for a probabilistic three-armed bandit task. They played in pairs, with the acting and observing player switching every one to three trials. An RL-learning algorithm was fit to participants' choices in the task to extract individual PE estimates for every trial of the experiment. In the acting condition, model-estimated PEs covaried positively with neural signal at electrode FCz, 200-350 ms after outcome presentation, which is a typical time frame for the FRN. There was no PE effect in the observation condition in the same time frame. From 300 ms the outcome correlated negatively with the frontal P300 component at FCz and parietal P300 at Pz. At Pz the effect was greater in the acting than the observing condition. The frontal and parietal P300 components have been linked to attentional reorienting and stimulus value updating, respectively. These findings indicate that observed outcomes undergo processing that is distinguishable from directly experienced outcomes in the time windows of the FRN and P3b but that attention dedicated to the two outcomes types is comparable.

Cortical beta power reflects decision dynamics and uncovers multiple facets of post-error adaptation.

Adapting to errors quickly is essential for survival. Reaction slowing after errors is commonly observed but whether this slowing is adaptive or maladaptive is unclear. Here, we analyse a large dataset from a flanker task using two complementary approaches: a multistage drift-diffusion model, and the lateralisation of EEG beta power as a time-resolved index of choice formation. Fitted model parameters and their independently measured neuronal proxies in beta power convergently show a complex interplay of multiple mechanisms initiated after mistakes. Suppression of distracting evidence, response threshold increase, and reduction of evidence accumulation cause slow and accurate post-error responses. This data provides evidence for both adaptive control and maladaptive orienting after errors yielding an adaptive net effect - a decreased likelihood to repeat mistakes. Generally, lateralised beta power provides a non-invasive readout of action selection for the study of speeded cognitive control processes.

Planning Your Way: How Humans Strategically Evaluate Prospective Decisions.

We are capable of planning ahead by incorporating dynamic factors influencing future choices. In this issue of Neuron, Kolling et al. (2018) present fMRI results of a novel task that demonstrates how humans evaluate alternative environments by prospectively incorporating their characteristics over time and account for their own decision tendencies.

Short-term reward experience biases inference despite dissociable neural correlates.

Optimal decision-making employs short-term rewards and abstract long-term information based on which of these is deemed relevant. Employing short- vs. long-term information is associated with different learning mechanisms, yet neural evidence showing that these two are dissociable is lacking. Here we demonstrate that long-term, inference-based beliefs are biased by short-term reward experiences and that dissociable brain regions facilitate both types of learning. Long-term inferences are associated with dorsal striatal and frontopolar cortex activity, while short-term rewards engage the ventral striatum. Stronger concurrent representation of reward signals by mediodorsal striatum and frontopolar cortex correlates with less biased, more optimal individual long-term inference. Moreover, dynamic modulation of activity in a cortical cognitive control network and the medial striatum is associated with trial-by-trial control of biases in belief updating. This suggests that counteracting the processing of optimally to-be-ignored short-term rewards and cortical suppression of associated reward-signals, determines long-term learning success and failure.

An Update on the Role of Serotonin and its Interplay with Dopamine for Reward.

The specific role of serotonin and its interplay with dopamine (DA) in adaptive, reward guided behavior as well as drug dependance, still remains elusive. Recently, novel methods allowed cell type specific anatomical, functional and interventional analyses of serotonergic and dopaminergic circuits, promising significant advancement in understanding their functional roles. Furthermore, it is increasingly recognized that co-release of neurotransmitters is functionally relevant, understanding of which is required in order to interpret results of pharmacological studies and their relationship to neural recordings. Here, we review recent animal studies employing such techniques with the aim to connect their results to effects observed in human pharmacological studies and subjective effects of drugs. It appears that the additive effect of serotonin and DA conveys significant reward related information and is subjectively highly euphorizing. Neither DA nor serotonin alone have such an effect. This coincides with optogenetically targeted recordings in mice, where the dopaminergic system codes reward prediction errors (PE), and the serotonergic system mainly unsigned PE. Overall, this pattern of results indicates that joint activity between both systems carries essential reward information and invites parallel investigation of both neurotransmitter systems.

Membrane localization of acetylated CNK1 mediates a positive feedback on RAF/ERK signaling.

Spatiotemporal control is a common mechanism that modulates activity and function of signal transducers in the signaling network. We identified acetylation of CNK1 (connector enhancer of kinase suppressor of Ras-1) as a late step in the activation of CNK1 signaling, accompanied with prolonged stimulation of extracellular signal-regulated kinase (ERK). We identified the acetyltransferase CREB (cyclic adenosine 3',5'-monophosphate response element-binding protein)-binding protein and the deacetylase SIRT2 (sirtuin type 2) as novel binding partners of CNK1, modulating the acetylation state of CNK1. Acetylation of CNK1 at position Lys414 located in the pleckstrin homology domain drives membrane localization of CNK1 in growth factor-stimulated cells. Inhibition of ERK signaling abolishes CNK1 acetylation. Cosmic database search identified CNK1 mutants at position Arg426 near the acetylation site in several human tumor types. These mutants show constitutive acetylation and membrane localization. CNK1 mutants substituting Arg426, the acetylation mimetic mutant CNK1-K414Q, and membrane-anchored CNK1 mutants all interact with the protein kinase CRAF and stimulate ERK-dependent cell proliferation and cell migration. In RAS-transformed cells, CNK1 is acetylated and membrane-bound and drives cell proliferation. Thus, growth factor-stimulated ERK signaling induces CNK1 acetylation, and acetylated CNK1 promotes ERK signaling, demonstrating a novel function of CNK1 as positive feedback regulator of the RAF/MEK (mitogen-activated protein kinase kinase)/ERK pathway. In addition, acetylation of CNK1 is an important step in oncogenic signaling, promoting cell proliferation and migration.